The liver is unique in its capacity to regenerate after resection or massive injury to restore original parenchymal mass, structure and function. Regeneration of the liver after resection or major injury is dependent upon a highly regulated sequence of molecular and cellular events. Cytokines and growth factors are known to serve as important signals controlling initiation and progression of hepatocyte proliferation and replication as well as termination of this process once liver mass has been restored. Much of our current knowledge regarding liver regeneration has been obtained using animal models of hepatectomy. While the information gained from these models has been invaluable, this model is not clinically relevant to liver recovery/regeneration after major injury, such as occurs after ischemia/reperfusion resulting from liver transplantation, resectional surgery or liver trauma. Ischemia/reperfusion represents a clinically relevant insultsignificant source of hepatocellular injury after ischemia/reperfusion. In models of hepatectomy, it has been shown that these same CXC chemokines directly stimulate hepatocytes to proliferate, thereby promoting liver regeneration. In contrast, our preliminary studies, using a model of hepatic ischemia/reperfusion, demonstrate that these chemokines are detrimental to liver recovery and regeneration. Furthermore, using cultured primary hepatocytes, we show that low concentrations of CXC chemokines prevent cell death whereas high concentrations promote cell death. Thus, the global hypothesis of this proposal is that the differential effects of CXC chemokines on hepatocyte proliferation and regeneration observed between hepatectomy and ischemia/reperfusion is directly related to the local concentration (expression) of CXC chemokines. In addition, we hypothesize that expression of the chemokine receptors, CXCR1 and CXCR2, differs in response to these insults and that this also contributeisting therapeutic agents that could have significant and immediate impact on the treatment of a number of liver diseases/disorders. PUBLIC HEALTH RELEVANCE: The studies outlined in this proposal are relevant to public health because they will define the molecular events by which CXC chemokines regulate hepatocyte proliferation and regeneration. The knowledge gained by these studies will provide the scientific basis for the clinical application of existing therapeutic agents that could have significant and immediate impact on the treatment of a number of liver diseases/disorders.